Striatal dysregulation of Cdk5 alters locomotor responses to cocaine, motor learning, and dendritic morphology

Douglas A. Meyer, Edmond Richer, Stanley A. Benkovic, Kanehiro Hayashi, Janice W. Kansy, Carly F. Hale, Lily Y. Moy, Yong Kim, James P. O'Callaghan, Li Huei Tsai, Paul Greengard, Angus C. Nairn, Christopher W. Cowan, Diane B. Miller, Pietro Antich, James A. Bibb

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39 Citations (Scopus)

Abstract

Motor learning and neuro-adaptations to drugs of abuse rely upon neuronal signaling in the striatum. Cyclin-dependent kinase 5 (Cdk5) regulates striatal dopamine neurotransmission and behavioral responses to cocaine. Although the role for Cdk5 in neurodegeneration in the cortex and hippocampus and in hippocampal-dependent learning has been demonstrated, its dysregulation in the striatum has not been examined. Here we show that strong activation of striatal NMDA receptors produced p25, the truncated form of the Cdk5 co-activator p35. Furthermore, inducible overexpression of p25 in the striatum prevented locomotor sensitization to cocaine and attenuated motor coordination and learning. This corresponded with reduced dendritic spine density, increased neuro-inflammation, altered dopamine signaling, and shifted Cdk5 specificity with regard to physiological and aberrant substrates, but no apparent loss of striatal neurons. Thus, dysregulation of Cdk5 dramatically affects striatal-dependent brain function and may be relevant to non-neurodegenerative disorders involving dopamine neurotransmission.

Original languageEnglish
Pages (from-to)18561-18566
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number47
DOIs
Publication statusPublished - 2008 Nov 25
Externally publishedYes

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Keywords

  • Addiction
  • Dopamine
  • Neurodegeneration
  • Spines
  • p25

ASJC Scopus subject areas

  • General

Cite this

Meyer, D. A., Richer, E., Benkovic, S. A., Hayashi, K., Kansy, J. W., Hale, C. F., Moy, L. Y., Kim, Y., O'Callaghan, J. P., Tsai, L. H., Greengard, P., Nairn, A. C., Cowan, C. W., Miller, D. B., Antich, P., & Bibb, J. A. (2008). Striatal dysregulation of Cdk5 alters locomotor responses to cocaine, motor learning, and dendritic morphology. Proceedings of the National Academy of Sciences of the United States of America, 105(47), 18561-18566. https://doi.org/10.1073/pnas.0806078105